Transient forebrain ischemia induces persistent hyperactivity of large conductance Ca2+‐activated potassium channels via oxidation modulation in rat hippocampal CA1 pyramidal neurons

Abstract The present study examined temporal changes in activity of large conductance, Ca 2+ ‐activated potassium (BK Ca ) channels in postischemic CA1 pyramidal neurons at 2, 6, 24 and 48 h after reperfusion. These changes in activity and possible cellular mechanisms were examined using the inside–out configuration of patch clamp. The unitary conductance of postischemic BK Ca channels increased transiently to 119% of the control at 2 h after reperfusion, and recovered to the control level thereafter. A persistent increase in [Ca 2+ ] i sensitivity of BK Ca channels was observed in postischemic CA1 neurons with the maximal sensitivity to [Ca 2+ ] i at 6 h after reperfusion while channel voltage‐ dependence showed no obvious changes. Kinetic analyses showed that the postischemic enhancement of BK Ca channel activity was due to longer open times and shorter closed times as there was no significant changes in opening frequency after ischemia. Glutathione disulphide markedly increased BK Ca channel activity in normal CA1 neurons, while reducing glutathione caused a decrease in BK Ca channel activity by reducing the sensitivity of this channel to [Ca 2+ ] i in postischemic CA1 neurons. Similar modulatory effects on postischemic BK Ca channels were also observed with another redox couple, DTNB and DTT, suggesting an oxidation modulation of BK Ca channel function after ischemia. The present results indicate that a persistent enhancement in activity of BK Ca channels, probably via oxidation of channels, in postischemic CA1 pyramidal neurons may account for the decrease in neuronal excitability and increase in fAHP after ischemia. The ischemia‐induced augmentation in BK Ca channel activity may be also associated with the postischemic neuronal injury.